1. Field of the Invention
The present invention relates to electrodes for electrically assisted drug delivery and a method for manufacturing the electrodes.
2. Description of the Related Art
Transmembrane delivery, typically transdermal delivery, increasingly has become a favored route for delivery of many drugs or other active compounds. One common form of transmembrane delivery is passive transdermal delivery in which a patch containing a reservoir of drug(s) or other compound(s) is applied to a patient""s skin. In passive transdermal drug delivery, a patch is suitably configured so that the compound will pass into, and commonly through, the patient""s skin. Passive transmembrane delivery also can be used for delivery to or through other bodily membranes, such as mucosa. However, passive delivery is limited due to the barrier properties of the stratum corneum.
Delivery of active ingredients through membranes, such as, without limitation skin, mucous membranes and nails may be facilitated by the application of an electric potential across the membrane. Iontophoresis and electroendosmosis are two forms of electrically assisted delivery. Typically, iontophoresis and electroendosmosis occur simultaneously to varying relative degrees whenever an electric potential is applied to a membrane, depending on the contents of the electrode reservoir and tissue-side composition. However, when the active ingredient to be delivered is ionic and transport is mainly due to charge transfer, the method typically is referred to as iontophoresis. In electrically assisted delivery, a reservoir containing the active ingredient, typically a drug, is placed on an anode or a cathode electrode that is connected to a source of electricity, such as a battery. In use, the drug-containing anode or cathode, the active or donor electrode, is applied to a membrane of a patient. An opposite electrode, also known as the return electrode, also is applied to a membrane of a patient to complete an electrical circuit. When a current is applied, the drug in the reservoir is delivered across the membrane. When the active ingredient is delivered from the anode, the delivery method is termed xe2x80x9canodic.xe2x80x9d When the active ingredient is delivered from the cathode, the drug delivery method is termed xe2x80x9ccathodic.xe2x80x9d
Electrically assisted delivery methods increasingly are considered for the delivery route of hydrophilic, large and charged molecules, as well as for peptides and proteins. The delivery can be localized or systemic. For instance, iontophoresis may be used for local delivery of anesthetics for IV catheterizations or for removal of skin lesions. However, systemic delivery is preferred for active ingredients such as hormones, insulin or pharmaceuticals such as opioids, nitroglycerine and nicotine.
PCT Patent publication WO 98/20869 discloses electrodes for the delivery of lidocaine and epinephrine. These active ingredients, being cationic under typical delivery conditions, are delivered from the anode reservoir. WO 98/20869 discloses an electrically assisted drug delivery system including an electric power supply, a donor anode and a return cathode. The anode contains a reservoir suitably configured to be in electrical contact with a patient""s skin containing a composition including lidocaine, epinephrine, an antioxidant, such as sodium metabisulfite, and a metal chelator, such as EDTA. The return cathode contains a reservoir suitably configured to be in electrical contact with a patient""s skin, containing a composition including sodium chloride and a buffer, such as a phosphate buffer.
One consideration in formulating compositions for iontophoretic drug delivery is that smaller, more mobile ions will decrease a given iontophoretic system""s ability to deliver larger drug ions. Thus, convention dictates that donor electrode reservoirs contain a minimal amount of small ionic species that are not active ingredients but have the same (positive or negative) charge as the active ingredient(s) under drug delivery conditions. U.S. Pat. No. 5,573,503 recognizes the inefficiencies in iontophoretic drug delivery caused by the presence of competing small ionic species (see, column 3, lines 42-60). That patent describes a method for eliminating those competing ions by using, in one example, silver/silver chloride (Ag/AgCl) electrodes in anodic donor electrode assemblies.
Reservoirs of donor electrodes may be manufactured by mixing or impregnating the active ingredient into a suitable matrix that typically is a polymer hydrogel. The impregnated gel is applied as a layer to the electrode, such as a Ag/AgCl electrode printed onto a polymeric surface. Although this is a common method for preparing iontophoretic electrodes, it may not be a preferred method due to the desirability and long-term stability of electrodes that are not pre-loaded with drug(s). These unloaded gels are later loaded with drug(s) by absorption and diffusion. Manufacturing efficiencies arising from this method include: 1) the ability to store unloaded gels for longer times as compared to typical loaded gels, permitting production of comparatively larger lots of unloaded gels, and 2) the ability to load sub-lots of the unloaded gels at different times, with different active ingredients and/or with different concentrations of active ingredient(s). Nevertheless, the method suffers from certain limitations. The solution loading process can result in ionic concentration differences along the electrode at the gel-electrode interface. When the electrode is exposed to different chloride concentrations, a concentration cell is established resulting in an electrochemical reaction that consumes Clxe2x88x92 and produces high concentrations of AgCl at certain sites and produces Ag and Clxe2x88x92 at the other low concentration sites. This redistribution of Ag and AgCl is detrimental as it can decrease the electrode capacity available for drug delivery. In use, the electrode capacity of the electrode may be exceeded in certain areas causing hydrolysis and pH burns. Furthermore, this type of localized corrosion can lead to the isolation of the electrodes from the interconnect traces leading to early failure of the patch. An electrode reservoir that can be loaded with drug without suffering from the formation of localized sites of electrode corrosion is therefore desired.
It has now been found that inclusion of sodium chloride or other salts, including organic salts, in an unloaded donor (active) electrode reservoir, prevents electrode corrosion during and resulting from loading of drug reservoirs by absorption and diffusion.
Thus, the present invention is directed to a donor electrode assembly for electrically assisted methods for delivery of active ingredients to patients. The electrode assembly contains a donor reservoir having a sufficient amount of a salt, for instance an alkaline metal halide salt, such as sodium chloride, to inhibit electrode corrosion. Also provided is a method of manufacturing of iontophoretic electrodes in which electrodes comprising unloaded donor reservoirs containing a predetermined amount of a salt such as NaCl, are loaded with an active ingredient by absorption and diffusion. Typically, drug delivery is anodic and the active ingredient typically contains chloride ions. In one instance, the active ingredient is lidocaine HCl, which is delivered with epinephrine in ionic form. By including salt essentially homogeneously in the unloaded reservoir, corrosion of the electrode resulting from loading reservoirs with active ingredient(s) is prevented.